The Use of Erythropoietin to Reprogram Oral and Craniofacial Stem Cells. This project directly addresses Challenge Area (14)-Stem Cells, specifically 14-DE-101* Reprogramming of Cells from Oral and Craniofacial Tissues in which we developed a novel approach for partial reprogramming of somatic stem cells of the oral and craniofacial complex using erythropoietin (Epo) for cell- based therapies to heal and restore these tissues following disease or trauma. We have identified that Epo is able to induce bone formation in vitro as well as in vivo. We have also purified mesenchymal stem cell (MSC) population that maintains its multi-lineage potential both in vivo and in vitro. Most importantly, we can isolate MSCs using cell surface markers that allows us to prospectively isolate the cells without culture. This sets us apart from others in the mesenchymal biology field. In this project we will combined our two studies to determine if Epo can partially reprogram adult MSCs to be used for regeneration of non-healing wounds This proposal will serve as a critical shift in our paradigm and a spring board for application of bioengineering to controlling tissue regeneration that we believe will ultimately be used in a broad range of human tissues. Our overall hypothesis is that erythropoietin (Epo) can be used to reprogram skeletal precursors and mesenchymal stem cells that can be harnessed for skeletal repair. Our approach will be to determine if Epo can be used to reprogram bone marrow stromal cells, and later MSCs, to facilitate osseous repair in nonhealing and irradiated critical sized boney defects. Aim 1. To determine the extent to which BMSCs reprogrammed to express EPO are capable of regenerating critical sized cranio-facial defects compromised by radiation therapy. Aim 2: To determine whether Epo can partially reprogram MSCs for cell-based therapies to heal and restore tissues following disease or trauma. This project will promote job creation, and accelerate the pace and achievement of science. The completion of the project is feasible in a two year timeframe and our group will then be in an outstanding position to propose and complete more mechanistic and translational studies in oral and craniofacial regeneration. 2 Erythropoietin can be used to reprogram skeletal precursors and mesenchymal stem cells that can be harnessed for skeletal repair.